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Abstract

Fatty acid (FA) is central energy substrate for the heart while glucose utilization is dynamically regulated in response to pressure-overload. We recently reported that capillary endothelial FABP4/5 play a critical role in FA uptake in the heart. FA uptake was reduced by 30% in the heart in FABP4/5 DKO (double knockout) as compared with WT (wild-type) mice while glucose uptake was 20-fold higher in DKO mice. In this study, we questioned how remarkable change of cardiac energy substrates (shift from FA to glucose) influences cardiac function under acute pressure overload by transverse aortic constriction (TAC). Seven days after TAC, cardiac contraction was significantly reduced in DKO mice whereas degree of hypertrophy and fibrosis was comparable. We next estimated uptake of FA tracer (125I-BMIPP) and glucose tracer (18F-FDG). In the presence of TAC, FA uptake was declined by 30% in WT heart while it was not changed in DKO. Glucose uptake was 10 fold-higher in WT heart compared with WT at baseline while it was 40-fold higher in DKO. Metabolome profiling further revealed remarkable change of metabolic flow by TAC. In the presence of TAC, a sum of metabolites in glycolysis was comparable whereas a sum of metabolites in TCA cycle was markedly reduced in DKO mice, indicating uncoupling between glucose uptake and TCA cycle. Consistent with this, phosphocreatine (reserve energy for adenosine triphosphate, ATP) was reduced by 40% in WT mice compared with WT at baseline while it was remarkably decreased by 80% in DKO. In contrast, amino acid (AA) synthesis (shown by ratio of alanine/pyruvate and glutamate/α-ketoglutarate) as well as FA synthesis (shown by ratio of malonyl-CoA/citrate) were significantly enhanced in DKO mice. Thus, markedly elevated uptake of glucose is more likely to be utilized for AA and FA biosynthesis rather than ATP production. In conclusion, an enhanced glucose utilization was not sufficient to compensate for reduced FA uptake in pressure-overloaded DKO heart at least partly because glucose was preferentially utilized for AA and FA biosynthesis. These findings suggest that ATP production is compromised for providing cellular building blocks during hypertrophic response in the condition of limited FA utilization with a marked increase in glucose uptake.